Myhre Syndrome

Clinical characteristics.

Myhre syndrome is a connective tissue disorder with multisystem involvement, progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, mild-to-moderate intellectual disability, and in some instances, autistic-like behaviors. Organ systems primarily involved include: cardiovascular (congenital heart defects, long- and short-segment stenosis of the aorta and peripheral arteries, pericardial effusion, constrictive pericarditis, restrictive cardiomyopathy, and hypertension); respiratory (choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease), gastrointestinal (pyloric stenosis, duodenal strictures, severe constipation); and skin (thickened particularly on the hands and extensor surfaces). Additional findings include distinctive craniofacial features and skeletal involvement (intrauterine growth restriction, short stature, limited joint range of motion). To date, 55 individuals with molecularly confirmed Myhre syndrome have been reported.

Diagnosis/testing.

The diagnosis of Myhre syndrome is established by detecting a de novo SMAD4 heterozygous pathogenic variant in a proband with characteristic clinical findings.

Management.

Treatment of manifestations: Symptomatic treatment (with attention to limiting tissue trauma by minimizing instrumentation during diagnosis and management) by specialty experts of the following involvement: cardiovascular, respiratory (including tracheostomy when tracheal stenosis is recurrent or complete), and GI; routine management of speech and language delay, intellectual disability, behavioral problems.

Prevention of secondary complications: Limiting of tissue trauma given the apparent increased risk for proliferative fibrosis following otherwise uncomplicated endotracheal intubation and surgical procedures. When possible, alternative noninvasive approaches should be pursued during diagnosis and management

Surveillance: Cardiovascular: echocardiogram every one to three years in asymptomatic individuals with a normal echocardiogram at the time of initial diagnosis; in individuals with abnormal cardiac findings at the time of diagnosis, more extensive imaging (including possible cardiac MRI) may be considered. Respiratory: oxygen saturation in children with monitoring as needed for symptoms suggestive of restrictive/obstructive pulmonary disease; annual pulmonary function studies in children oldert than age six years if able to cooperate; evaluation of laryngotracheal stenosis based on symptoms. Annual ophthalmology and audiology evaluations.

Agents/circumstances to avoid: Smoking; tissue trauma.

Genetic counseling.

Myhre syndrome is inherited in an autosomal dominant manner. All probands with Myhre syndrome reported to date have the disorder as a result of a de novo SMAD4 pathogenic variant. If the SMAD4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism. To date, individuals with Myhre syndrome are not known to reproduce and fertility has not been assessed. Once the SMAD4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at theoretic increased risk for Myhre syndrome and preimplantation genetic diagnosis are possible.

Suggestive Findings

Myhre syndrome should be suspected in individuals with the following clinical and radiographic findings.

Clinical

Cardiovascular

• Arterial obstruction: juxtaductal coarctation of the aorta, long- and short-segment descending thoracic and abdominal aortic obstruction, and peripheral arteries in various locations; infrequently, branch pulmonary artery stenosis
• Congenital heart defects:
  • Atrial and ventricular septal defects, patent ductus arteriosus
  • Valvular stenosis: aortic and mitral valves; infrequently, tricuspid and pulmonic valves
• Pericardial involvement: ranges from effusion to constrictive pericarditis; often chronic and severe
• Restrictive cardiomyopathy (can be rapidly progressive)
• Hypertension: systemic and pulmonary

Respiratory (congenital or acquired)

• Laryngotracheal narrowing (including subglottic stenosis)
• Choanal stenosis
• Obstructive airway disease
• Restrictive pulmonary disease (which appears to increase with age)

Gastrointestinal

• Congenital or acquired pyloric stenosis
• Later onset:
  • Duodenal strictures
  • Severe constipation

Skin

• Stiff and thickened overall, but particularly on the hands and extensor surfaces
• Facial creases fewer than expected for age

Proliferative fibrosis/scarring

• May occur spontaneously or following trauma or surgery
• May involve the serosal surfaces of the heart, airway and lungs, and gastrointestinal tract as well as the skin

Neuropsychiatric

• Mild-to-moderate intellectual disability
• Autistic-like behaviors in some

Craniofacial

• Characteristic facial features including short palpebral fissures, deeply set eyes, maxillary underdevelopment, short philtrum, narrow mouth, thin vermilion of the upper lip, and prognathism (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5). Facial characteristics can progress over time; although classic coarsening of features is not present, mandibular elongation is notable. Note: Craniofacial features can vary considerably.
• Cleft lip and/or palate and velopharyngeal insufficiency reported in 13% [Lin et al 2016]

Figure 1.

Female with Myhre syndrome at ages seven months, four years, and 16 years. Note the short palpebral fissures, thin upper vermilion border and maxillary underdevelopment. She required tracheostomy subsequent to traumatic intubations that resulted in complete (more...)

Figure 2.

Female with Myhre syndrome at ages newborn, 12 months, 3.5 years, and seven years. Note the short palpebral fissures, thin upper vermilion border, and progression of mild prognathism.

Figure 3.

Female with Myhre syndrome at ages three years, ten years (standing), and 21 years (face, posterior hairline, and hands). Note the short palpebral fissures, broad mid-upper nasal bridge, downward pointing nasal tip, thin upper vermilion border, broad (more...)

Figure 4.

Male with Myhre syndrome at age 12 years. Note the mild facial features (mild maxillary underdevelopment and thin upper vermilion border) and finger contractures (hands are on a flat surface).

Figure 5.

Female with Myhre syndrome at age five years. Note the short palpebral fissures, thin upper and lower vermilion borders, left-sided facial palsy, and brachydactyly with otherwise mild features. Facial palsy is observed in 4% of individuals with Myhre (more...)

Skeletal

• Infants typically have intrauterine growth restriction (IUGR)
• Short stature (height is significantly less than that predicted by parental heights) with compact body habitus
• Range of motion of the joints can be limited

Radiographic

Findings include the following:

• Thickened calvarium
• Shortened long bones
• Brachydactyly
• Broad ribs
• Enlarged vertebrae with shortened pedicles; vertebral fusion
• Hypoplastic iliac wings

See Figure 6.

Figure 6.

Radiographs of a female age 14 years A. Thickened calvaria and anterior cervical vertebral fusion (arrow) of C2 and C3.

Establishing the Diagnosis

The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a de novo heterozygous pathogenic variant in SMAD4 detected by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genome sequencing).

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Myhre syndrome is a multisystem connective tissue disorder involving: the cardiovascular system, respiratory system, gastrointestinal tract, and skin; progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, often resulting in significant complications; mild-to-moderate intellectual disability; and behavioral issues in some. Additional findings include distinctive craniofacial features and skeletal involvement.

Myhre syndrome was first described by Myhre et al [1981] in two unrelated males. Since 2011, when heterozygosity for a SMAD4 pathogenic variant was found to be causative, 55 affected individuals with a molecularly confirmed diagnosis of Myhre syndrome have been reported. Lin et al [2016] reported four affected individuals and summarized findings in 50 previously reported individuals [Le Goff et al 2011, Al Ageeli et al 2012, Asakura et al 2012, Caputo et al 2012, Lindor et al 2012, Picco et al 2013, Ishibashi et al 2014, Kenis et al 2014, Michot et al 2014, Hawkes & Kini 2015, Oldenburg et al 2015, Starr et al 2015]. Subsequently Bassett et al [2016] reported one additional affected individual.

Note: Unless otherwise noted, the following findings are reported in Lin et al [2016].

Infancy and progression of findings. In infancy, characteristic facial features are usually present, but more difficult to recognize than in an older child (see Suggestive Findings and Figure 1, Figure 2, Figure 3, Figure 4, Figure 5). Short stature and hearing loss develop over time as well as the highly distinctive (and often severe) findings of Myhre syndrome: joint stiffness, restrictive lung and cardiovascular disease, progressive and proliferative fibrosis, and thickening of the skin.

Cardiovascular. Of 54 individuals with a confirmed molecular diagnosis of Myhre syndrome, 70% had a cardiovascular abnormality including structural heart defects (63%); pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%).

Cardiovascular abnormalities include the following:

• Atrial septal defect (4%) and ventricular septal defect (6%)
• Patent ductus arteriosus (which can be large) (20%)
• Obstructive defects of the left heart, such as juxtaductal aortic coarctation (15%), long-segment aorta narrowing (6%), aortic valve stenosis (15%), and mitral valve stenosis (2%). These are more common than obstructive defects of the right-side, such as valvar and branch pulmonary artery stenosis [Michot et al 2014, Hawkes & Kini 2015, Starr et al 2015].
• Peripheral vascular stenoses (in celiac and/or renal arteries) (7%)

Of note, complex congenital heart defects are not observed.

Pericardial disease (reported in 17%) can present as a short-term or recurrent effusion or as chronic or progressive constrictive pericarditis that may require surgical intervention (see Management).

Restrictive cardiomyopathy, a lethal condition, is the least common form of cardiomyopathy in the general population and can be overlooked unless cardiac catheterization documents the characteristic hemodynamics.

While constrictive pericarditis and restrictive cardiomyopathy can present with similar hemodynamics, they differ in pathogenesis and treatment (see Management).

Pulmonary hypertension has been infrequently reported; however, this may reflect limited evaluation and/or bias toward ascertainment and/or reporting of younger patients (as underlying causes of pulmonary hypertension resulting from involvement of the lungs and cardiovascular circulation may evolve with age).

Progressive cardiovascular issues can appear at any age; those with onset in childhood may worsen following instrumentation: two patients with restrictive cardiomyopathy who were treated with heart and heart/lung transplantation did not survive postoperative complications [Starr et al 2015].

Respiratory. Respiratory issues can be multifactorial. Airway stenosis, typically involving the larynx and trachea, has included subglottic stenosis (17%) that can be recurrent and severe. Less common is upper airway obstruction due to choanal stenosis (11%).

Restrictive and obstructive pulmonary disease are major causes of morbidity at all ages. Interstitial lung disease has been described. Severe pulmonary fibrosis has been noted on autopsy [Starr et al 2015].

Gastrointestinal involvement

• Duodenal atresia 3/54 (6%)
• Late-onset pyloric stenosis [L Starr, personal observation]
• Protein-losing enteropathy (Patient 1 [Lin et al 2016])
• Severe constipation [Michot et al 2014, Starr et al 2015]

Cutaneous. Generalized thickening/stiffness of the skin is seen in nearly all individuals with Myhre syndrome. Various terms used to describe the skin include thick, stiff, firm, rough, keratotic, and inelastic. Additional findings are minimal creasing of the facial skin and fibrous and keloid-like scar formation.

Skin changes may not be apparent in infancy; they are often first noted on extensor surfaces, palms, and soles. The changes progress with age.

Neuropsychiatric. Data are limited. Mild-to-moderate intellectual disability and developmental delay are common; however, cognition can be within the normal range. Of note, acquired and unrecognized hearing loss may also contribute to speech delay and academic and social challenges.

Findings of autism spectrum disorder have been noted in a minority of affected individuals [Michot et al 2014].

Skeletal. The majority of affected infants have intrauterine growth restriction (41/49; 84%). Short stature with compact body habitus (with normal head circumference) becomes more apparent over time. Adult height is expected to be more than two standard deviations below what is predicted by parental heights.

Small hands and feet with brachydactyly is usually notable (see Figure 3, Figure 4, Figure 5).

Posture may be distinct with flexed elbows and bending forward at the hips (see Figure 3 and Ishibashi et al [2014], Figure 1).

Reduced range of motion of large and small joints is characteristic and is exacerbated with age. Walking on tiptoes is common.

Immune system. Recurrent infections (especially otitis media and pneumonia) have been reported in 19 of 34 individuals. Increased susceptibility to infection has been associated with immunoglobulin deficiency in three affected individuals; IVIG was utilized with reported benefit in one affected individual [Starr et al 2015]. At this point, it is unknown if immune deficiency is associated with Myhre syndrome or if it is an incidental finding [Michot et al 2014, Starr et al 2015].

Ophthalmologic. At least one abnormal eye finding was reported in 53% (26/49) of affected individuals:

• Strabismus 13/53 (24%)
• Refractive errors in 17/53 (31%)
• Other. Cataracts, astigmatism, and optic nerve sheath meningioma

Hearing loss is observed in most (83%) individuals with Myhre syndrome.

Hearing loss is predominantly conductive, but can be sensorineural and mixed. The underlying etiology of the hearing loss is often unclear or unknown; most often patients have a history of bilateral myringotomy tube placement.

Of note, most infants pass their newborn hearing screen. In the authors' experience hearing loss usually becomes evident in early childhood and is typically present in adults.

Endocrine. Puberty has been reported to be normal, premature, or delayed. Secondary amenorrhea has been reported.

Neoplasia

• Endometrial carcinoma [Lindor et al 2012], optic nerve sheath meningioma [Starr et al 2015], and mesencephalic glioma [Lin et al 2016] have each been reported once.
• Telangiectasias and juvenile polyps, reported in heterozygotes for a SMAD4 loss-of-function pathogenic variant, have not been reported in Myhre syndrome; however, information to date is limited.

Genotype-Phenotype Correlations

The gain-of-function SMAD4 pathogenic variants that cause Myhre syndrome involve only two protein residues (codons 496 and 500). To date, no clear genotype-phenotype correlations are evident in affected individuals with either codon abnormality.

Of note, although the three individuals reported with the p.Arg496C variant do not have cardiovascular involvement and are taller in stature – two on the growth curve (2^nd-25^th centile) and one <1^st centile [Michot et al 2014, Caputo et al 2014] – the data are too limited to draw any conclusions about genotype-phenotype correlations.

Penetrance

Penetrance appears to be complete; however, no familial cases of Myhre syndrome have been reported.

Nomenclature

LAPS (laryngotracheal stenosis, arthropathy, prognathism, and short stature) syndrome was determined to be a phenotypic variant of Myhre syndrome with pathogenic variants in the same codons [Lindor et al 2012, Picco et al 2013, Michot et al 2014]; the term is no longer in use.

Prevalence

The prevalence is unknown.

Since 2011 when a heterozygous pathogenic variant in SMAD4 was discovered to be the cause of Myhre syndrome, 55 affected individuals with a molecularly confirmed diagnosis have been reported worldwide with no apparent ethnic or sex predilection (54 summarized in Lin et al [2016] and one reported by Bassett et al [2016]).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Myhre syndrome, the following are recommended (if not completed previously as part of the diagnostic evaluation).

Cardiovascular

• Upper- and lower-extremity blood pressure measurements
• Two-dimensional echocardiography with Doppler
• For those with abnormal findings, more extensive imaging if indicated including cardiac catheterization to document the characteristic hemodynamics of restrictive cardiomyopathy

Respiratory

• Assessment for airway stenosis by the least invasive means possible with assessment for signs of upper-airway obstruction including noisy breathing, work of breathing, and oxygen saturation
• Assessment of pulmonary function and oxygen saturation for evidence of obstructive or restrictive lung disease

Gastrointestinal. Based on clinical indication (by least invasive means possible), evaluate for evidence of stenosis.

Neuropsychiatric. Neuropsychometric evaluation may be indicated for individuals with autistic behaviors and/or cognitive involvement.

Other

• Ophthalmology evaluation
• Speech evaluation
• Audiology evaluation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is largely symptomatic and may include the following.

Cardiovascular

• Management by a cardiologist trained in congenital heart disease, including pericardial disease and restrictive cardiomyopathy. At present, no evidence suggests that in Myhre syndrome management of specific lesions would differ from standard care in current clinical practice, except that any unnecessary instrumentation should be avoided as associated tissue trauma may induce stenosis and the scarring-type tissue response unique to Myhre syndrome.
• Affected individuals who are in heart failure should be under the care of a cardiovascular specialist with access to a transplant center.
• Maximize all medical treatment and minimize instrumentation for all cardiac studies and therapies.
• Medical treatment of systemic hypertension and pulmonary hypertension (based on underlying cause).

Respiratory

• Affected individuals have required long-term tracheostomy due to complete and recurrent tracheal stenosis following multiple and/or traumatic intubations [McGowan et al 2011, Oldenburg et al 2015, Starr et al 2015]. To avoid traumatic intubation, consider using a size-smaller uncuffed endotracheal tube. Elective tracheal surgery/intubation should be avoided; tracheal resection is contraindicated [Oldenburg et al 2015].
• Symptomatic treatment of restrictive lung disease
• Oxygen supplementation as necessary

Gastrointestinal

• Minimal instrumentation of the gastrointestinal tract is advised because post-operative adhesions can be fatal [Lindor et al 2012].
• Endoscopy should be approached with caution to avoid airway manipulation which increases the risk for tracheal/laryngeal scarring/stenosis [Oldenburg et al 2015]. Noninvasive 3D imaging may be preferred.
• Aggressive management of constipation (through dietary means or medication if necessary) is indicated.

Prevention of Secondary Complications

Limiting tissue trauma appears to be the single most important preventive measure: The literature suggests increased risk of proliferative fibrosis following otherwise uncomplicated endotracheal intubation and surgical procedures. When possible, alternative noninvasive approaches should be pursued during diagnosis and management [Oldenburg et al 2015, Starr et al 2015].

• Extreme care with intubation and use of an endotracheal tube without a cuff (or careful monitoring of pressures with a cuff) may help prevent airway stenosis [Oldenburg et al 2015].
• Minimize abdominal and pelvic procedures as extensive adhesions may develop postoperatively [Lindor et al 2012].
• Hysterectomy should be an option of last resort for treatment of menorrhagia as post-surgical fibrosis is highly likely.

Surveillance

Cardiovascular

• After normal baseline evaluations of upper- and lower-extremity blood pressure measurements, two-dimensional echocardiography with Doppler, and cardiology evaluation
• In asymptomatic individuals with a normal echocardiogram at the time of initial diagnosis, repeat echocardiogram every 1-3 years. Note that pericardial effusion and restrictive cardiomyopathy may occur at any age and may be clinically asymptomatic [Starr et al 2015, Garavelli et al 2016, Lin et al 2016].
• In individuals with abnormal findings at the time of initial diagnosis, more extensive imaging may be indicated given the progressive nature of the disorder (e.g., MRI to evaluate for pericardial thickening or effusion).

Respiratory

• Consider oxygen saturation in children, with monitoring as needed for symptoms suggestive of restrictive/obstructive pulmonary disease and annual pulmonary function studies in children older than age six years if able to cooperate with test maneuvers.
• Evaluation for upper airway stenosis (e.g., laryngotracheal stenosis) should be considered based on symptoms.

Other

• Annual ophthalmologic and audiology evaluations
• Monitoring of physical skill development and joint mobility

Agents/Circumstances to Avoid

Patients should be aggressively counseled not to smoke.

Limiting tissue trauma appears to be the single most important preventive concept in this disorder to communicate to all health care providers involved in their care (see Prevention of Secondary Findings).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.